title: Pharmacological characterization of BR-A-657, a highly potent nonpeptide angiotensin II receptor antagonist.
abstract: The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [(125)I][Sar(1)-Ile(8)]angiotensin II (Ang II) from its specific binding sites to AT1 subtype receptors in membrane fractions of HEK-293 cells with an IC50 of 0.16 nM. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD'2: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A-657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.
authors.affiliation: Central Research Institute, Boryung Pharm. Co., Ltd, Gyoenggi 425–839, Republic of Korea.
authors.forename: Yong Ha
authors.initials: YH
authors.lastname: Chi
authors.forename: Joo Han
authors.initials: JH
authors.lastname: Lee
authors.forename: Je Hak
authors.initials: JH
authors.lastname: Kim
authors.forename: Hyun Kwang
authors.initials: HK
authors.lastname: Tan
authors.forename: Sang Lin
authors.initials: SL
authors.lastname: Kim
authors.forename: Jae Yeol
authors.initials: JY
authors.lastname: Lee
authors.forename: Hong-Kun
authors.initials: HK
authors.lastname: Rim
authors.forename: Soo Heui
authors.initials: SH
authors.lastname: Paik
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D011743:Pyrimidines; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C558933:fimasartan